Optimizing the Diagnosis and Biomarker Testing for Patients with Intrahepatic Cholangiocarcinoma: A Multidisciplinary Approach

Abstract

Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the treatment paradigm for these patients. However, several challenges exist to the seamless adoption of precision medicine in patients with CCA, relating to a lack of awareness of the importance of biomarker testing, hurdles in tissue acquisition, and ineffective collaboration among the multidisciplinary team (MDT). To identify gaps in standard practices and define best practices, multidisciplinary hepatobiliary teams from the University of California (UC) Davis and UC Irvine were convened; discussions of the meeting, including optimal approaches to tissue acquisition for diagnosis and biomarker testing, communication among academic and community healthcare teams, and physician education regarding biomarker testing, are summarized in this review.

Biliary stem cells in health and cholangiopathies and cholangiocarcinoma

“…This classification is based on the anatomical organization of the intrahepatic biliary tree and recapitulates the level or size of the displayed bile duct. Different intrahepatic cholangiocarcinoma (iCCA) histological subtypes can be identified, including large bile duct type [which histologically resembles perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA)] and small bile duct type, which comprises also the so called cholangiolocarcinoma [72–75]. The molecular alterations of CCA ranges from SNVs, insertions and deletions, to copy number alterations and chromosome rearrangements/functions [76–82,83 ▪ ,84,85].…”

“…There is a wide heterogeneity of the molecular alterations based on anatomical classification [76–82,83 ▪ ,84,85]. From the point of view of markers for target therapies, intrahepatic CCA is among the tumors with the greatest actionable mutations, in particular IDH1/2, FGFR2, whereas p/dCCA present a very low percentage of cases with actionable mutations, mainly in ERBB2 [75–82,83 ▪ ,84,85]. Notably, etiology of chronic biliary or hepatic inflammation impact strongly on the molecular pathogenesis [79].…”

An Expert, Multidisciplinary Perspective on Best Practices in Biomarker Testing in Intrahepatic Cholangiocarcinoma

“…Approximately 40% to 50% of patients with iCCA are expected to have potentially actionable targets, including genetic aberrations in isocitrate dehydrogenase-1 ( IDH1 ; 10-20%), fibroblast growth factor receptor 2 ( FGFR2 ; 10-16%), BRAF mutations (<5%), NTRK fusions (<5%), and MSI-H/dMMR, TMB >10 mutations/megabase (<5%) 14 ( Table 1 ). Targeted therapies with selective inhibitors have demonstrated clinical efficacy and safety in iCCA.…”

“… *The percentages provided are approximations. Source: Cho et al 14 Abbreviations: dMMR, deficient mismatch repair; FGFR, fibroblast growth factor receptor; IDH1, isocitrate dehydrogenase-1; MSI, microsatellite instability; TMB, tumor mutational burden. …”

A new biomarker panel for differential diagnosis of cholangiocarcinoma: Results from an exploratory analysis

“…1 Mortality rates for CCA have been increasing worldwide and patients generally have a very poor prognosis, with 5-year survival rates of only 7-20%. 2 Increases in mortality in recent years have largely been driven by iCCA, with mortality from eCCA either plateauing or falling. 3 Given that CCA has long been associated with parasitic liver fluke infections, prevalence is highest in East Asia where these infections are endemic.…”